Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals.
In mammals, the circadian clock relies on interlocked feedback loops involving clock genes and their protein products. Post-translational modifications control intracellular trafficking, functionality and degradation of clock proteins and are keys to the functioning of the clock as recently exemplified for the F-Box protein Fbxl3. The SCF(Fbxl3) complex directs degradation of CRY1/2 proteins and Fbxl3 murine mutants have a slower clock. To assess whether the role of Fbxl3 is phylogenetically conserved, we investigated its function in the sheep, a diurnal ungulate. Our data show that Fbxl3 function is conserved and further reveal that its closest homologue, the F-Box protein Fbxl21, also binds to CRY1 which impairs its repressive action towards the transcriptional activators CLOCK/BMAL1. However, while Fbxl3 appears to be ubiquitously expressed, Fbxl21 expression is tissue-specific. Furthermore, and in sharp contrast with Fbxl3, Fbxl21 is highly expressed within the suprachiasmatic nuclei, site of the master clock, where it displays marked circadian oscillations apparently driven by members of the PAR-bZIP family. Finally, for both Fbxl3 and Fbxl21 we identified and functionally characterized novel splice-variants, which might reduce CRY1 proteasomal degradation dependent on cell context. Altogether, these data establish Fbxl21 as a novel circadian clock-controlled gene that plays a specific role within the mammalian circadian pacemaker.
Dardente
Hugues
H
School of Biological Sciences, Aberdeen University, Aberdeen, Scotland, United Kingdom. h.dardente@abdn.ac.uk
Mendoza
Jorge
J
Fustin
Jean-Michel
JM
Challet
Etienne
E
Hazlerigg
David G
DG
D000595:Amino Acid Sequence; D000818:Animals; D001683:Biological Clocks / Q000235:genetics* / Q000502:physiology; D019556:COS Cells; D002417:Cattle; D002522:Chlorocebus aethiops; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D056931:Cryptochromes; D024721:E-Box Elements; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005420:Flavoproteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008322:Mammals / Q000235:genetics / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D012756:Sheep / Q000235:genetics* / Q000502:physiology
C538963:CRY1 protein, human; C538964:Cry1 protein, mouse; D056931:Cryptochromes; D044783:F-Box Proteins; C519794:Fbxl3 protein, mouse; D005420:Flavoproteins